2-methyl-2-hydroxy-4-(2, 2, 2-trichloro-1-hydroxyethoxy)-pentane and its production



United States aren't 2-METHYL-2-HYDROXY-4-(2,2,2-TRICHLORO-1-HY-DROXYETHOXY)=PENTANE AND ITS PRODUC- TION Jorgen Erik Tind Christensen,Hellerup, near Copenhagen, Denmark, assignor to Bet Danske Medicinal- &Kemikalie-Kompagni A-S, Copenhagen, Denmark No Drawing ApplicationNovember 26, 1957 Serial No. 699,143

Claims priority, applicationDenmark December 8,1056

SClaims. (Cl. 260 -4515) The present invention relates to a new chloralderivative and the production thereof. 3

Although chloral hydrate is the oldest of the synthetic hypnotics it isstill in use as a very reliable hypnotic with a sure and pleasant effectwithout unpleasant after-elfects.

After the introduction of the barbituric acid derivatives, the use ofchloral hydrate decrease somewhat owing to the disadvantages connectedwith its actual use as a hypnotic. Thus it has a penetrating andunpleasant smell and taste, but is at the same time too 'hygroscopic tobe conveniently dispensed in capsules or tablets. Moreover, anadministration in capsules or tablets would hardly ice is dependant onvarious factors, such as perature and particle size. I The new chloralderivative has no irritating effect. A freshly. made suspension in waterleaves no necrosis on being injected subcutaneously. The derivative is,however, particularly useful as a hypnotic for administration in tabletssince the said hydrolysis, taking place in the gastrointestinal tract,proceedsat a suitably slow rate, so that there are never at any timelarger amounts of chloral hydrate causing irritation of the mucousmembrane of the stomach, the hydrolysis on the other hand being so rapidthat the hynotic effect is not notably delayed. Clinical experiments,comprising a larger number of patients, have perfectly confirmed this.

Prior to the clinical experiments, a number of animal tests were carriedout, in which the'effects of the new derivative were compared with thoseof chloral hydrate.

In one such experiment, a group of mice was given doses of 500 mg.chloral hydrate per kilogram, and another group was given correspondingdoses of the new derivative. The average anaesthesia time (50% of theanimals awake) proved to be 150 minutes for the animals which were givenchloral hydrate, and 200minutes for those given the new derivative.

In another experiment, the amounts of organic bound stirring,temchlorine excreted in the urine were determined in a group beadvisable on account of the local irritating effect which the substanceexerts on the mucous membrane of the stomach.

In the course of time, numerous attempts have been made to producechloral derivatives not having the said disadvantages, but retaining thebeneficient properties of the chloral as a hypnotic. However, none ofthe hitherto produced derivatives have been so satisfying as to bringthem into general use, and it is still most common to administer chloralhydrate in aqueous solution, the solution being extremely diluted inorder to mitigrate the local irritating effect.

According to the present invention there is provided a newchloral'derivative which is. 2-methyl-2-hydroxy-4-(2,2,2-trichloro-I-hydroxyethoxy)-pentane of the formula According tothe invention, this chloral derivative can be prepared by reactingchloral, chloral hydrate or a chloral alcoholate with2-methyl-2,4-pentanediol with or without a solvent being present.

The chloral derivative forms colourless and odourless or substantiallyodourless crystals of a slightly bitter taste.

' water, but is hydrolized in aqueous solution according to For totaldissolution, i.e. hydrolysis, of the chloral derivative at roomtemperature at least about 3.5 parts of water are needed. Of course, therate of the hydrolysis of 4 rabbits. First, 2 g. of chloral hydrate wereadministered to each rabbit by means of a stomach tube. After 48 hoursalmost no chlorine was found in the urine. The average recovery was 69%.Then, each of the animals was given 3.2 g. of the new derivative(corresponding to 2 g. of chloral hydrate). Here. the average recoveryof organic bound chlorine was 60%.

In a corresponding experiment with 4 healthy human subjects, two ofwhich were given doses of 1 g. and the other two of 2 g. calculated aschloral hydrate, the average recovery was 25% after administrationofchloral hydrate, and 22% after administration of the new derivative.

A toxicity determination on mice showed, as would be expected, that thetoxicity was near to but, however, a little below the toxicity of theamount of free chloral hydrate which corresponds to the chloral contentof the derivative. Thus, the LD 50 for the free chloral hydrate wasdetermined to 21 mg. per 25 g. mice, whereas LD 50 for chloral in theshape of the present chloral derivative was determined to 23 mg.,corresponding to 37 mg. derivative, per 25 g. mice.

In the clinical trial of the new derivative, the attention wasparticularly directed to the observation of secondary effects. 7

The derivative was used as a hypnotic in series of patients sufferingfrom severe sleeplessness, mainly chronic neurotics of a complainingtype. The usual hypnotic (a barbiturate) was substituted by 2 tablets,each containing 0.40 g. of the new derivative, corresponding to 0.25 g.of chloral hydrate. None of the patients reacted to the change, andthere were no gastric upsets.

Five patients were given the new derivative as a sedative during theday, one tablet as above being given in the morning, one at noon, andtwo in the evening. This dose was given daily for about 6 months. Thenormal clinical analyses were carried out. No albuminuria was observed.

Five patients being given 2 tablets daily for more than 3 months showednormal haemoglobin and red cells. The white blood cells were found to bebetween 5000 and 8000 per cubic millimeter blood.

The 2-methyl-2,4-pentanediol which is used in preparing the presentcompound is a substance which is widely used as a solvent, and accordingto the available information it must be considered substantiallynon-toxic and exempt of any local irritating effect by administration inthe proportions in question here.

lowing examples:

, The method of the invention is'illustrated by the fol- Exa mple l 6590 g.-of 2-methyl 2,4-pentanediol (5 moles) are mixed with 3 litres oftetrachlorornethane, and 737 g. of

1269 g. (about 95%).

Example-.2

472 g. of 2-methyl-2,4-pentanediol (4" moles) are heated to 70 to 8O, C.in a bowl, and 660 g. of chloral hydrate (4 moles) are added. Thetemperature, which decreases during the addition, is then increased to60 to 70 C. under continuous stirring until all of the chloral hydrateis dissolved, and the stirring is continued at a somewhat lowertemperature. When the reaction mixture-hasbecome a nearly dry crystalpowder, this powder is subjected to further drying by slight heating.The weight of the final raw product will be'about 1060 g., correspondingto theweight of the two components less 4 moles H Owhich are formed bythe reaction. Recrystallization is carried out from tetrachloromethane,and the yield is 980 g. (about 92% Instead of chloral ,hydrate', forexample, chloral ethanolate may be used in an amount of 774 g. (4moles). The method is carried out in the same manner, the onlydifference being that in this case 4 moles of ethanol is formed insteadof 4 moles of water.

Iclaim:

1. As a compound,2-methyl-2-hydroXy-4-(2,2,2-trichloro-1-hydroxyethoxy)-pentane.

2. A method for the production of 2-methyl-2-hydroxy-4-(2,2,2-trichloro-l-hydroxyethoxy)-pentane, in which chloral-is addedto a solution of 2-methyl-2,4-pentanediol in tetrachloromethaneat roomtemperature.

3. A method for the production of Z-methyl-Z-hydroxy- 4-2,2,2-trichlorol-hydroxyethoxy -pentane comprising mixing equi-molecularproportions of chloral with 2- methyl-2,4-pentanediol intetrachloromethane, stirring the mixture at room. temperature to promotecrystallization, and filtering off the resulting crystals.

4. A method for the production of 2-methyl-2-hydroxy-4-(2,2,2-trichloro-l-hydroxyethoxy)-pentane comprising heatingZ-mthyl-ZA-pentanediol to a temperature of 70 to 80 C., adding chloralhydrate in equimolecular proportions to react with the2-methyl-2,4-pentanedio1, continuously stirring the mixture of chloralhydrate and 2-methyl-2,4-pentanediol while maintaining the temperatureat to C. until all of the chloral hydrate is dissolved, and continuingstirring of the reaction mixture until the latter becomes a dry crystalpowder.

5. A method for the production of 2-methyl-2-hydroxy-4-(2,2,2-trichloro-l-hydroxyethoxy)-pentane, comprising heating2-methyl-2,4-pentanediol to a temperature of 70 to C., adding chloralethanolate in equimolecular proportions to react with the2-methyl-2,4-pentanediol, stirring the reactants while maintaining thetemperature at 60' to 70 C. until all of the chloral ethanolate is dissolved, and continuing to stir thereactants until a dry crystal powderis formed therefrom.

References Cited in the file of this patent UNITED STATES PATENTS OTHERREFERENCES Gatski: American Practitioner and Digest of Treatment, vol.6, No. 12 (1955), pp. 1885-1891.

1. AS A COMPOUND,2-METHYL-2-HYDROXY-4-(2,2,2-TRICHLORO-1-HYDROXYETHOXY)-PENTANE.